Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen, China.
Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen, China; Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China.
Exp Cell Res. 2018 May 1;366(1):71-80. doi: 10.1016/j.yexcr.2018.03.016. Epub 2018 Mar 13.
Protocadherins (Pcdhs) are widely-expressed transmembrane proteins in the nervous system. Recent studies suggest that Pcdhs play multiple critical roles during neuronal development. However, the cellular mechanisms of Pcdh7 in neurons are still largely unknown. In the current study, we demonstrated that the expression of Pcdh7 during mouse brain development was regulated spatiotemporally. We observed that the elevated expression of Pcdh7 led to activation of the intrinsic apoptotic pathway in primary cortical neurons. Whole transcriptome sequencing revealed that 12 genes were involved in the apoptotic pathway including baculoviral inhibitor of apoptosis (IAP) repeat containing 5 (BIRC5). The neuronal apoptosis caused by Pcdh7 overexpression could be significantly inhibited by either a missense mutation in the conserved motif CM2 domain of Pcdh7 or BIRC5 overexpression. These results suggest the existence of Pcdh7-BIRC5 signaling cascade in the cortical neurons and represent a potential therapeutic area for further investigation.
原钙黏蛋白（protocadherins，Pcdhs）是神经系统中广泛表达的跨膜蛋白。最近的研究表明，Pcdhs 在神经元发育过程中发挥多种关键作用。然而，Pcdh7 在神经元中的细胞机制在很大程度上仍不清楚。在本研究中，我们证明了 Pcdh7 在小鼠大脑发育过程中的表达受到时空调节。我们观察到 Pcdh7 的表达上调导致原代皮质神经元中内在凋亡途径的激活。全转录组测序显示，包括杆状病毒 IAP 重复包含蛋白 5（baculoviral inhibitor of apoptosis repeat containing protein 5，BIRC5）在内的 12 个基因参与了凋亡途径。Pcdh7 过表达引起的神经元凋亡可以通过 Pcdh7 保守模体 CM2 结构域中的错义突变或 BIRC5 过表达显著抑制。这些结果表明，Pcdh7-BIRC5 信号级联在皮质神经元中存在，代表了进一步研究的潜在治疗领域。
